By David N. Leff
Just as women have periodic mammograms to catch breast cancer early, people at risk of colorectal cancer undergo visual checkups of their large intestine's wall by endoscopy.
What the gastroenterologist expects to find is not so much tumors as their precursors polyps. The long, flexible tube that inspects the five or six feet of the colon carries a light, viewing lenses and small snips or snares to remove any polyps discovered.
People susceptible to colon cancer, either through heredity or exposure to carcinogens, may harbor hundreds, even thousands, of polyps studding their colon wall, each capable of becoming a tumor. This precancerous condition is known as adenomatous polyposis coli. Its APC acronym also names APC the tumor suppressor gene that discourages polyps from turning malignant. (See BioWorld Today, Dec. 18, 1997, p. 1.)
But all too often, that APC gene goes over to the enemy. It mutates and becomes an oncogene.
Colorectal cancer, along with prostate, breast and lung, ranks among the four most common cancers in the U.S. This year it will strike more than 131,000 men and women, and some 56,000 individuals will die of the disease.
"Just eight years ago," recalled molecular oncologist Kenneth Kinzler, we didn't even know about APC mutations. Now we know this type of mutation is one of the earliest genetic changes in most colon cancers, and we know what it does to c-MYC." Kinzler directs the Johns Hopkins [University] Oncology Center, in Baltimore.
He and his associate, Bert Vogelstein, are co-senior authors of a paper in today's Science, dated Sept. 4, 1998, titled "Identification of c-MYC as a target of the APC pathway."
Every person carries the c-MYC oncogene, but it lies dormant in the colon until APC's inactivation as a tumor suppressor awakens it.
"Cancer is like a car with the accelerator pushed to the floor and failing brakes," observed Vogelstein. "In this case, c-MYC is the accelerator, and APC the failed brakes. When suppressor genes like APC malfunction," he explained, "cells get signals to continue multiplying until they are out of control. Now we know that in colon cancer a mutated APC gene signals to c-MYC."
The Science paper's first author, postdoctoral molecular geneticist Tong-Chuan He, told BioWorld Today that "myc is genetically overexpressed in 70 to 80 percent of colon cancer cells." This overexpression in other tumor types has been attributed to chromosomal rearrangement or gene amplification. "But most of the colon cancers," He pointed out, "don't have this amplification or rearrangement. So the mechanism was really unknown."
SAGE Fingered MYC In Gene Line-Up
To clear up this mystery, He employed SAGE serial analysis of gene expression a technique invented by Vogelstein and Kinzler, and licensed by the university to Genzyme Corp., of Cambridge. Mass. SAGE counts cellular messenger RNAs, a measure of gene expression.
"In my SAGE analysis to profile all the genes," He recounted, "the one on top was the myc."
APC messages its c-myc target to proliferate via two relay molecules, beta-catenin and T-cell factor 4 (Tcf-4). "Beta-catenin," He explained, "is a cellular protein, which can interact with a lot of other proteins, including APC. It's something like a cell-adhesion molecule.
"One of beta-catenin's functions," he continued, "is to heterodimerize with another transcription factor, called Tcf-4, and then to activate downstream genes, like a transcription complex. We identified c-myc as the first target by this transcription factor and complex."
Wild-type APC, the Hopkins team found, repressed c-MYC expression; beta-catenin activated it, via Tcf-4 binding to the c-MYC promoter.
He defined the principal finding of the Science article as "establishing a previously unknown link between the prominent tumor supressor gene, APC, and the prominent oncogene, c-myc. It has implications for tumor research and also for clinical treatment of colon cancer."
In this context, He recalled attending a meeting where he presented a paper on the Science article's data. "Someone from a small biotech company in Massachusetts contacted me," he said. "[The person] suggested that maybe we could find some compound to down-regulate myc expression. It's one of the several options that can be done in the future."
He foresees "constructing a myc reporter gene from its promoter, and using it to screen therapeutic compounds to down-regulate myc activity in cancer cells. So, down the line, I think this has implications for biotech companies." *